Multiple myeloma (MM) is a fatal, clonal B-cell malignancy of terminally differentiated immunoglobulin-secreting plasma cells (PCs) that originate in germinal centers of lymph nodes and home to and expand in the bone marrow. Although other hematological malignancies have been molecularly classified by cytogenetic abnormalities, historically, molecular analysis of MM has been difficult. However, using high-density oligonucleotide DNA microarray (HDA) technology on RNA isolated from highly purified PCs, expression profiles of nearly 6800 genes in normal and malignant MM PCs, as well as monoclonal gammopathy of undetermined significance (MGUS), have been established. Building on preliminary data from more than 70 newly diagnosed MM patients and 7 MGUS cases, new molecular-based diagnostic and prognostic models of the plasma cell dyscrasia MGUS and MM will be established. This goal will be accomplished through 3 specific aims. 1. Define gene expression patterns that differentiate normal, pre-neoplastic, and neoplastic plasma cells. 2. Develop diagnostic and prognostic models for MGUS and MM by use of gene expression profiles. 3. Define the molecular signatures of disease evolution and resistance/relapse through longitudinal global gene expression studies. A new molecular classification of MM and related disorders, provided through the proposed work, will enable clinicians and bench scientists to better understand and combat plasma cell cancer on a genetic level. This knowledge will not only allow a better under- standing of the basic biological pathways that are altered in MM and MGUS but also will provide the framework for the creation new highly accurate molecular tests to diagnose and predict prognosis of these diseases as well aid in the design of novel therapeutics. Thus, the work proposed supports the goals of an R33 project funded through PAR-01-106 (Applications of Innovative Technologies for the Molecular Analysis of Cancer).